It has been known for some time that a variety of cancers are caused, at least in part, by mutations to certain normal genes, termed "proto-oncogenes." Proto-oncogenes are involved in regulating normal cell growth in ways that are only now beginning to be appreciated at the molecular level. The mutated proto-oncogenes, or cancer causing genes termed "oncogenes," disrupt normal cell growth which ultimately causes the death of the organism, if the cancer is not detected and treated in time.
During normal or cancer cell growth, proto-oncogenes or oncogenes, are counterbalanced by growth-regulating proteins which regulate or try to regulate the growth of normal or cancer cells, respectively. Such proteins are termed "tumor suppressor proteins." A number of such proteins are known.
A gene that encodes a tumor suppressor protein termed p53 is frequently mutated in a number of human cancers, and the inactivation of p53 is thought to be responsible for the genesis or progression of certain cancers (Nigro et al., 1989, Nature 342:705-708), including human colorectal carcinoma (Baker et al., 1989, Science 244:217-221), human lung cancer (Takahashi et al., 1989, Science 246:491-494; Iggo et al., 1990, Lancet 335:675-679), chronic myelogenous leukemia (Kelman et al., 1989, Proc. Natl. Acad. Sci. USA 86:6783-6787) and osteogenic sarcomas (Madsuda et al., 1987, Proc. Natl. Acad. Sci. USA 84:7716-7719). Tumor cells that exhibit p53 are more sensitive to radiation treatment than tumor cells that have little or no p53.
Unfortunately, knowledge of the p53 status of tumors has not translated into new or more effective treatments for cancer. There are, however, reports showing that when p53 is supplied to a tumor cell that lacks p53, or expresses a non-functional mutated form of the molecule, certain types of breast and lung cancer cell lines exhibit normal cell growth, or undergo cell death. See Casey et al., Oncogene, vol. 6: 1791-1797 (1991), and Takahasi et al., Cancer Research, vol. 52: 2340-2342 (1992). These observations have stimulated efforts aimed at supplying to p53 minus cancer cells DNA that encodes wild type p53 via virus based gene transfer vehicles with the aim of causing the cancer cells to exhibit the normal cell phenotype, or undergo cell death. Unfortunately, the viral vectors that have been used to do these gene transfer experiments do not replicate in the host cancer cells that would effect the transfer of the p53 gene to neighboring cancer cells. Thus, for p53 gene therapy to be maximally successful every cancer cell in a patients' body must receive and express the DNA that encodes wild-type p53. To date this has not been achieved.
Another drawback relating to the delivery of tumor suppressors using viral vectors is the rejection of the vectors by a patient's immune system. Indeed, recent gene therapy trials with recombinant adenovirus carrying the gene that encodes the cystic fibrosis transmembrane conductance regulator protein were halted because of rejection of adenoviral proteins by the patients' immune system.
It has recently been described by McCormick (PCT/US94/02049, filed Feb. 16, 1994) that a recombinant adenovirus, dl1520, produced by Barker and Berk Virology vol.156: page 107-121 (1987), selectively replicates and lyse p53 minus cancer cells but not normal cells. Moreover, newly replicated virus was shown to be competent to infect and lyse neighboring cancer cells. Thus, in at least one respect, this finding is a marked advance over current gene therapy approaches which, to be maximally effective require that all cancer cells be infected following viral infection. This method, nevertheless, shares the drawback with the gene therapy approaches of immunologic rejection of the viral vector by the patient.
Thus, it is apparent that there is an unmet need for treating cancer, and particularly cancers that would respond favorably to treatment that takes advantage of the tumor suppressor status of a tumor, and that is not limited by a patient's immune system.